PDLIM2 as a cancer and chemosensitizing target

PDLIM2 作为癌症和化疗增敏靶点

• 批准号: 8575709
• 负责人: GUTIAN XIAO
• 金额: $ 31.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575709
• 关键词: Adjuvant Therapy; Adult; Applications Grants; Breast; Cancer Etiology; Carboplatin; Cessation of life; Chemosensitization; Clinical Trials; Colon; Colon Carcinoma; DNA; DNA Methyltransferase; DNA Modification Methylases; Development; Diagnosis; Epigenetic Process; Gene Targeting; Genetic Transcription; Goals; Growth; Human; Immune response; In Vitro; Knock-out; LIM Domain; Lead; Link; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular; Multi-Drug Resistance; Mus; Nuclear; Pathogenesis; Patients; Pharmaceutical Preparations; Physiological; Physiology; Platinum; Play; Prevention; Proteins; RNA; Recruitment Activity; Repression; Research; Resistance; Role; Smoking; T-Cell Leukemia; Testing; Therapeutic; Translating; Tumor Suppressor Proteins; Tumorigenicity; United States; anticancer research; base; cancer cell; cancer therapy; cancer type; chemosensitizing agent; chemotherapy; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; leukemia/lymphoma; lung cancer prevention; lung tumorigenesis; mutant; new therapeutic target; novel; novel diagnostics; novel strategies; outcome forecast; p65; preclinical study; prevent; promoter; public health relevance; reconstitution; response; transcription factor; tumor; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Chemotherapy remains the standard first-line treatment for many cancers, including lung cancer, the leading cause of cancer deaths responsible for approximately 160,000 deaths every year in the United States alone. However, the benefits of current chemotherapy are very limited due to intrinsic and acquired resistance of cancer cells. The long-term goal of our research is to understand the mechanisms underlying tumorigenesis and chemoresistance, and to translate this understanding into novel approaches to improve cancer cure rates by establishing new effective therapies and/or priming cancer cells to respond to current therapeutic drugs. To this end, we have recently identified PDLIM2, a ubiquitously expressed PDZ-LIM domain-containing protein with the highest level in lungs, as a suppressor of lung cancer and several other cancer types such as adult T-cell leukemia/lymphoma (ATL), breast, and colon cancers. We find that the expression of PDLIM2 is epigenetically repressed in these cancer cells, and that PDLIM2 reconstitution prevents their tumorigenicity. Moreover, PDLIM2 deficiency predisposes mice to spontaneous and induced cancers, particularly lung cancer. Notably, the repression of PDLIM2 expression is associated with the chemotherapy resistance of lung cancer, and PDLIM2 re-induction is required for the epigenetic drug 5-aza-dC to induce growth inhibition and response to the chemotherapeutic drug carboplatin in multidrug resistant lung cancer cells. Mechanistic studies indicate that PDLIM2 functions as a ubiquitin E3 ligase to selectively degrade nuclear (activated) NF- ?B RelA (also known as p65), a transcription factor that has been suggested to play a causative role in tumorigenesis and therapeutic resistance of multiple human cancers, including ATL, breast, colon and lung. Based on these innovative findings, we hypothesize that PDLIM2 repression leads to constitutive NF-?B activation, which in turn contributes to cancer pathogenesis and therapy resistance. In this application, we aim to (1) determine the molecular mechanisms by which PDLIM2 expression is repressed in lung cancer; (2) elucidate the mechanistic role of PDLIM2 in lung cancer development; and (3) examine the role and mechanisms of PDLIM2 in lung cancer chemosensitivity and therapy. These studies are innovative and significant, because they will greatly increase our understanding of the tumorigenesis and chemoresistance of lung cancer, and may form a novel class of PDLIM2-based epigenetic approaches as a primary or adjuvant therapy for lung cancer prevention and treatment. In particular, clinical trials show that it is impractical to block NF-?B activation for cancer therapy using 'classical' NF-?B inhibitors because of the importance of NF-?B in human physiology. However, PDLIM2 prevents pathogenic but not physiological activation of NF-?B by terminating NF-?B activation. Consistently, PDLIM2 expression, although repressed in cancer cells, is high under physiological conditions. Thus, PDLIM2-based therapies will effectively alleviate NF-?B-mediated tumorigenesis and chemoresistance while keeping the physiological functions of NF-?B, such as immune responses, intact in patients. Moreover, it is feasible to target PDLIM2 for cancer therapy because our studies show that the repression of PDLIM2 expression in cancer cells is pharmacologically reversible.

描述（由申请人提供）：化疗仍然是许多癌症（包括肺癌）的标准一线治疗方法，肺癌是癌症死亡的主要原因，仅在美国每年就造成约16万人死亡。然而，由于癌细胞的内在和获得性耐药，目前化疗的益处非常有限。我们研究的长期目标是了解肿瘤发生和化疗耐药的机制，并通过建立新的有效疗法和/或启动癌细胞对当前治疗药物的反应，将这种理解转化为提高癌症治愈率的新方法。为此，我们最近发现了PDLIM2，一种普遍表达的含PDZ-LIM结构域的蛋白，在肺中表达水平最高，作为肺癌和其他几种癌症类型（如成人t细胞白血病/淋巴瘤（ATL）、乳腺癌和结肠癌）的抑制因子。我们发现PDLIM2的表达在这些癌细胞中受到表观遗传抑制，并且PDLIM2的重组阻止了它们的致瘤性。此外，PDLIM2缺乏使小鼠易患自发性和诱发性癌症，特别是肺癌。值得注意的是，PDLIM2表达的抑制与肺癌的化疗耐药有关，表观遗传药物5-aza-dC在多药耐药肺癌细胞中诱导生长抑制和对化疗药物卡铂的反应需要PDLIM2的再诱导。机制研究表明，PDLIM2作为泛素E3连接酶选择性降解核（活化）NF- ？B RelA（也称为p65）是一种转录因子，已被认为在包括ATL、乳腺癌、结肠癌和肺癌在内的多种人类癌症的肿瘤发生和治疗耐药中起致病作用。基于这些创新的发现，我们假设PDLIM2抑制导致构构性NF-？B活化，这反过来又有助于癌症的发病和治疗耐药性。在这项应用中，我们的目标是：(1)确定肺癌中PDLIM2表达被抑制的分子机制；(2)阐明PDLIM2在肺癌发生发展中的作用机制；(3)研究PDLIM2在肺癌化疗敏感性和治疗中的作用和机制。这些研究具有创新性和重要意义，因为它们将大大增加我们对肺癌肿瘤发生和化疗耐药的理解，并可能形成一类基于pdlim2的新型表观遗传学方法，作为肺癌预防和治疗的主要或辅助治疗方法。特别是，临床试验表明，阻断NF-？B活化